DESCRIPTION (Applicant's Abstract) One of the most significant health problems in our country relates directly to the consequences of pain. Estimates suggest that as many as 30 million Americans suffer from chronic pain which is resistant to medical treatment. One of the chronic abnormal pain states which is extremely difficult to treat is commonly referred to as "neuropathic pain." Our understanding of this condition is limited, but has been increased in recent years by development of animal models in which injuries are made to peripheral nerves to produce signs which reflect some aspects of human neuropathic pain states. A striking result of these injuries is a substantial increase in the expression of spinal dynorphin. It is known that dynorphin may rapidly be degraded to des-Tyr fragments which do not interact with opioid receptors and that dynorphin can produce a significant number of effects which are non-opioid in nature. This proposal is aimed at testing the hypothesis that the spinal dynorphin is intimately involved in either the initiation or maintenance of nerve-injury related pain through non-opioid mechanisms. This hypothesis will be systematically tested by (a) measurement of whether and when dynorphin expression occurs in the spinal cord following specific nerve injuries; (b) determination of the functional consequences of spinal dynorphin and its role in maintenance of the post-injury state; (c)determination of the consequences of preemptive inhibition of dynorphin activity to evaluate its role in initiation of the nerve-injury consequences; (d) identification of a mechanism by which dynorphin may produce such pathological actions via interaction with a novel binding site on the NMDA receptor complex; and (e) direct evaluation of the effects of dynorphin on the viability of neurons. The present studies should reveal much about the role of dynorphin in post-injury processes in the spinal cord. It is expected that treatments that prevent the expression of spinal dynorphin or that block the actions of pathological levels of dynorphin at a specific site on the NMDA receptor complex should provide additional therapeutic benefit in the treatment of neuropathic pain.